Highly regioselective Vilsmeier-Haack acylation of hexahydropyrroloindolizine

Full text of DOI:10.1021/jo001769x

2522
J . Org. Chem. 2001, 66, 2522-2525
Sch em e 1
High ly Regioselective Vilsm eier -Ha a ck
Acyla tion of Hexa h yd r op yr r oloin d olizin e
Babak Sayah, Nadia Pelloux-Le´on, Anne Milet,
J ose´phine Pardillos-Guindet, and Yannick Valle´e*
LEDSS, Universite´ J oseph Fourier-CNRS, B.P. 53,
38041 Grenoble, France
Yannick.Vallee@ujf-grenoble.fr
Received December 20, 2000
Myrmicaria ants, a genus of African Myrmicinae,
produce a series of poisonous alkaloids containing the
hexahydropyrroloindolizine ring system.1 The simplest
members of this new family (Scheme 1) are the ethyl
propyl derivative named myrmicarin 217 (M217) and the
(Z)- and (E)-ethylpropenyl derivatives M215A and M215B.
The first synthesis of racemic M2172 was reported by
Schro¨der and Francke (which previously isolated the
various natural myrmicarins),1 and we recently described
a synthesis of nonracemic (R)-(+)-M217.3
Sch em e 2
Formally, M215A,B and M217 can be regarded as
derived from the unsubstituted compound 1 via two
regioselective electrophilic aromatic substitutions. For
instance, M217 would be formed by a regioselective
ethylation on C4, followed by the introduction of the
propyl group on C3 (Scheme 1). Alternatively, the propyl
group could be first regioselectively linked to C3, and the
ethyl group entered in second. To overcome the possible
problem of double alkylation (for instance, substitution
by two ethyl groups) in the first step of these syntheses,
as well as the possible rearrangement of the propyl
cation, it would probably be more efficient to use acyla-
tion reactions, rather than alkylation reactions, each
acylation being followed by a reduction step of the
obtained ketone into the needed alkyl group. The obvious
question is then: can some regioselectivity be expected
for an acylation reaction on a substrate that looks so
quasi-symmetric? With two goals in mind, the major one
being to give a (positive) answer to this question and the
other one being to determine if myrmicarins could be
synthesized this way, we decided to study some acylation
reactions of compound 1.
The authors presented steric arguments to explain their
observations.5 Furthermore, even some substitution on
the poorly reactive C7 was noticed and the results
depended largely on the used conditions (including the
order of introduction of the reagents!). This was not very
encouraging for our particular case. However, we tested
some Friedel-Crafts acetylation reactions with com-
pound 1.
The first results were very disappointing, but not for
the reason we were expecting. When 1 was treated with
acetyl chloride (1.0 equiv) in the presence of aluminum
trichloride (2.5 equiv), the only isolated product (yield
50%) was the diacetylated compound 3c (Scheme 2).
Neither of the two regioisomeric monoacetylated com-
pounds was isolated. This was not specific to the tricyclic
compound 1; when the same reaction was conducted with
1,2,5-trimethylpyrrole 4, the obtained product was the
diacetyl trimethylpyrrole 5.6 No traces of the monoacetyl
derivative were noticed.
Only a few studies have been conducted on similar
questions. In the 1980s, two French teams published
their results about the Friedel-Crafts acetylation of
tetrahydroacenaphtene 2, the analogue of the pyrrole
We were more successful with Vilsmeier-Haack reac-
tions7 (Table 1). For instance (entry 1), when 1 was
treated with dimethylacetamide (1.0 equiv) and POCl3
(1.0 equiv) in dichloroethane at room temperature for 24
h, the two regioisomers 3a ,b were isolated as an unsepa-
rable mixture in 70% yield. No diacetylated derivative
3c was noticed. The ratio 3a /3b, determined by 1H NMR,
derivative 1 in the benzene family.4 They reported only
poor selectivities, generally in favor of acetylation on C8.
(2) Schro¨der, F.; Francke, W. Tetrahedron 1998, 54, 5259.
(3) Sayah, B.; Pelloux-Le´on, N.; Valle´e, Y. J . Org. Chem. 2000, 65,
2824.
(4) Gruber, R.; Cagniant, D.; Cagniant, P. Bull. Soc. Chim. 1983,
93.
(5) Gruber, R.; Kirsch, G.; Cagniant, D. Bull. Soc. Chim. 1987, 498.
(6) Bright, J . J . Am. Chem. Soc. 1957, 79, 3200.
(7) Gangjee, A.; Patel, J .; Kisliuk, R.; Gaumont, Y. J . Med. Chem.
1992, 35, 3678.
(1) Francke, W.; Schro¨der, F.; Walter, F.; Sinnwell, V.; Baumann,
H.; Kaib, M. Liebigs Ann. 1995, 965. Schro¨der, F.; Francke, S.; Francke,
W.; Baumann, H.; Kaib, M.; Pasteels, J . M.; Daloze, D. Tetrahedron
1996, 52, 13539. Schro¨der, F.; Sinnwell, V.; Baumann, H.; Kaib, M. J .
Chem. Soc., Chem. Commun. 1996, 2139. Schro¨der, F.; Sinnwell, V.;
Baumann, H.; Kaib, M.; Francke, W. Angew. Chem., Int. Ed. Engl.
1997, 36, 77.
10.1021/jo001769x CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/30/2001

Notes
J . Org. Chem., Vol. 66, No. 7, 2001 2523
Ta ble 1. Yield s a n d Ra tios Obta in ed in Vilsm eier -Ha a ck Acyla tion s u n d er Differ en t Rea ction Con d ition s
solvent, T (°C),
reaction time (h)
monoacylated compds,
yield (%)
ratio
C4/C3
diacylated compd,
yield (%)
entry
R1
R2
1
2
3
4
5
6
7
8
9
10
11
12
13d
Me
Me
Me
Me
H
Et
Pri
But
H
H
H
H
H
Me
Me
Me
Pri
Me
Me
Me
Me
Me
Me
Me
Me
Me
C2H4Cl2, rt, 24
C2H4Cl2, 83, 3
toluene, 83, 3
C2H4Cl2, 83, 24
C2H4Cl2, 83, 2
C2H4Cl2, 83, 3
C2H4Cl2, 83, 24
C2H4Cl2, 83, 24
cyclohexane, 83, 4
toluene, rt, 4
3a ,b, 70
3a ,b, 70
3a ,b, 71
3a ,b, 70
6a ,b, 70
7a ,b, 75
8a ,b, 65
9a ,bc
6a ,b, traces
6a ,b, 70
6a ,b, 53
6a ,b, 72
6a ,b, 80
80/20
84/16
80/20
70/30
86/14
70/30
55/45
30/70c
b
a
a
a
a
a
a
a
a
6c, 42
6c, 3
6c, 18
a
97/3
>99/1
93/7
toluene, 83, 2
CH2Cl2, 40, 3
CH2Cl2, 40, 3
86/14
a
a
b
d
Not observed. Not determined. c Not separated from byproducts. Reaction with 2.0 equiv of DMF, 2.0 equiv of POCl3.
Sch em e 3
was 80/20. Thus, in contrast with the results reported
for the Friedel-Crafts acetylation of tetrahydroacenaph-
tene 2, the observed regioselectivity largely favored the
substitution on the carbon nearing the saturated six-
membered ring; i.e., if we accept and extrapolate to this
case the arguments presented in refs 4 and 5 on the more
hindered carbon. Indeed, examination of the results
presented in Table 1 indicates that the bulkier the
Vislmeier reagent, whether because of its R1 group (for
instance, compare entries 2, 5, 6, 7, and 8), or because of
its R2 nitrogen substituents (compare entries 2 and 4),
the more important is the proportion of the product
acetylated on C3. This confirms that C3, nearing the five-
membered ring, suffers less steric constraint than C4.
The influence of temperature for reactions conducted
in dichloroethane was quite low (entries 1 and 2). In
contrast, changes of the solvent had a dramatic influence
on the course of the formylation reaction. The most
impressive change was the exclusive formation of the
diformylated product 6c when the solvent was cyclohex-
ane (entry 9). No traces of 6c were noticed when the
reaction was conducted in C2H4Cl2 or CH2Cl2, even when
2.0 equiv of Vilsmeier reagent was used (entry 13). Our
interpretation of these results is that in polar solvents
the product formed in the reaction mixture, before
hydrolysis, probably has the iminium structure A. This
When it was used as the solvent (entry 11), the major
product was monoformylated; however, some diformy-
lated pyrrole 6c was also isolated. What is more im-
portant here is the surprisingly high regioselectivity
reached: the only isolated monoformylated compound
was the isomer 6a . As 6a is easily separated from 6c,
this method can be regarded as useful for the synthesis
of myrmicarins.
Thus, 6a was treated with methyllithium, and in the
same pot, the resulting alcoholate was reduced by LiAlH4,
giving the ethyl derivative 10 (Scheme 3). 10 was
formylated under Vilsmeier conditions, and the obtained
aldehyde was treated with the Wittig reagent obtained
from ethyltriphenylphosphonium bromide. In this way,
a mixture of M215A and B was obtained (ratio A(Z)/
B(E): 4/1) in 45% yield from 6a . This is the first reported
synthesis of M215.
We undertook some theoretical calculations to deter-
mine why position 4 of 1 was more reactive than position
3. The population analysis through both the Mulliken and
NBO schemes exhibited nearly no charge difference
between the two carbons (-0.32e for C3 against -0.33e
for C4 using the NBO scheme). Similarly, examination
positively charged species cannot undergo any further
electrophilic substitution. We propose that the product
is much more covalent in nonpolar solvents and might
be well described by structure B. B is a neutral pyrrole
bearing one more substituent, as compared to the start-
ing tricycle 1. Thus, B might be more nucleophilic than
1. This would explain the exclusive formation of 6c.
Toluene is slightly more polar than cyclohexane (but
considerably less polar than the chlorinated solvents).

2524 J . Org. Chem., Vol. 66, No. 7, 2001
Notes
H-5), 3.90-3.95 (m, 1H, H-7a), 5.85 (s, 2H, H-3 and H-4); 13C
NMR (75 MHz; CDCl3) δ 21.5 (C-5), 22.8 (C-2), 25.3 (C-7), 30.1
(C-1), 37.9 (C-6), 55.7 (C-7a), 99.7 (C-4), 105.8 (C-3), 123.3, 132.0;
MS (CI) 148 (MH.+). Anal. Calcd for C10H13N: C, 81.59; H, 8.9;
N, 9.51. Found: C, 81.49; H, 8.88; N, 9.50.
Sch em e 4
(7a R)-3,4-Dia cetyl-1,2,5,7,7a -h exa h yd r op yr r olo[2,1,5-cd ]-
in d olizin e (3c). A solution of 1 (100 mg, 0.68 mmol) was added
to a suspension of aluminum chloride (300 mg, 2.24 mmol) in
dry CH2Cl2 (7 mL) and acetyl chloride (0.64 mL, 0.748 mmol).
The resulting mixture was refluxed for 2 h, poured onto crushed
ice, and stirred until melted. The layers were separated, and
the aqueous one was extracted 3 times with CH2Cl2. The
combined organic layers were dried (MgSO4) and evaporated.
Column chromatography on silica gel of the residue gave pure
compound 3c (75 mg, yield: 50%): [R]20 ) +68.6 (c 0.50, CH2-
D
Cl2); IR (NaCl) 1657 (CO) cm-1; mp 152 °C; 1H NMR (300 MHz;
CDCl3) δ 1.23-1.38 (m, 1H, H-7), 1.71-1.78 (m, 1H, H-6), 2.02-
2.09 (m, 1H, H-1), 2.09-2.17 (m, 1H, H-6), 2.17-2.22 (m, 1H,
H-7), 2.38 (s, 3H, CH3), 2.40 (s, 3H, CH3), 2.63-2.73 (m, 1H,
H-1), 2.73-2.79 (m, 1H, H-2), 2.97-3.00 (m, 1H, H-2), 3.00-
3.05 (m, 2H, H-5), 3.88-3.91 (m, 1H, H-7a); 13C NMR (75 MHz;
CDCl3) δ 20.5 (C-6), 21.4 (C-2), 26.0 (C-5), 27.7 (C-7), 28.6 (CH3),
29.7 (CH3), 35.0 (C-1), 55.2 (C-7a), 117.5, 122.1, 131.0, 138.6,
192.8 (CO), 196.2 (CO); MS (CI) 232 (MH.+). Anal. Calcd for
C14H17NO2: C, 72.70; H, 7.40; N, 6.05. Found: C, 72.75; H, 7.45;
N, 6.05.
Gen er a l Exp er im en ta l P r oced u r e for Vilsm eier -Ha a ck
Acyla tion of Com p ou n d 1. A solution of 1 (1.0 equiv) in a dry
solvent was added at room temperature to a mixture of amide
(1.0 equiv) and POCl3 (1.0 equiv) in the same solvent. The
resulting solution was stirred. The reaction was carried on until
the initial product had totally disappeared on TLC. Aqueous
NaOH (10%) was added, and the mixture was stirred for 15 min.
The solution was cooled, diluted with water, and extracted with
CH2Cl2. The organic layer was dried (MgSO4) and evaporated.
The residue was purified by chromatography on silica gel (CH2-
Cl2/AcOEt, 9:1).
of molecular orbitals showed only a small difference in
favor of an attack on C4. More interestingly, a clear
difference was found between the two cations resulting
from the protonation of 1 on C4 and C3. These cations C
and D mimic the cationic intermediate obtained in the
first step of the Vilsmeier-Haack reaction (Scheme 4).
The energy difference between C and D was found to be
3.1 kcal/mol at the B3LYP level of calculation with the
6-31G* basis set (HF: 3.3 kcal/mol; MP2:2.8 kcal/mol
using the same basis set). The cation formed on the six-
membered ring is more stable than the one formed on
the other side. This can be interpreted in terms of the
greater ring strain in the iminium form of cation D, with
a CdN double bond included in the five-membered ring,
and is consistent with our experimental findings. Thus,
we propose that the regioselectivity of these Vilsmeier-
Haack reactions is explained by the greater stability of
the cationic intermediate resulting from an attack on C4.
Finally, we think that the total regioselectivity ob-
served for the formylation of 1 in toluene at 83 °C (Table
1, compare entries 10 and 11) should be interpreted as a
consequence of the partial double formylation observed
in this apolar solvent. The second formylation is probably
easier when it creates a cationic intermediate on the six-
membered ring. Thus, the intermediate resulting from a
first attack on C3 is double formylated more rapidly than
the other one. This would explain why we isolated only
6a and 6c, and no 6b.
(7a R)-4-Acetyl-1,2,5,6,7,7a -h exa h yd r op yr r olo[2,1,5-cd ]in -
1
d olizin e (3a ): IR (NaCl) 1657 (CO) cm-1; H NMR (500 MHz;
CDCl3) δ 1.24-1.28 (m, 1H, H-7), 1.72-1.77 (m, 1H, H-6), 1.94-
1.98 (m, 1H, H-1), 2.10-2.18 (m, 1H, H-6), 2.18-2.20 (m, 1H,
H-7), 2.35 (s, 3H, CH3), 2.53-2.57 (m, 1H, H-1), 2.70-2.79 (m,
2H, H-2), 2.79-2.83 (m, 1H, H-5), 3.10-3.17 (m, 1H, H-5), 3.81-
3.87 (m, 1H, H-7a), 6.17 (s, 1H, H-3); 13C NMR (75 MHz; CDCl3)
δ 20.1 (C-6), 21.8 (C-5), 23.1 (C-2), 25.2 (CH3), 27.8 (C-7), 35.8
(C-1), 54.0(C-7a), 101.1 (C-3), 121.2 (C-4), 137.8, 149.9, 194.6
(CO); MS (CI) 190 (MH.+).
Str u ctu r e Deter m in a tion of 3a . Apart from the signals
corresponding to the aromatic protons at δ ) 6.17 and 6.19 ppm,
the one-dimensional 1H NMR spectrum of compounds 3 showed
overlapping signals of aliphatic protons. According to the integral
values, the chemical shift of the aromatic proton of the major
regioisomer was δ ) 6.17 ppm. To determine the structure of
3a , several two-dimensional NMR experiments were envisaged.
Exp er im en ta l Section
All commercial solvents were distilled before use. THF was
distilled from sodium benzophenone ketyl under nitrogen at-
mosphere. Toluene was distilled from sodium under nitrogen
atmosphere. Methylene chloride (CH2Cl2) and 1,2-dichloroethane
(C2H4Cl2) were distilled from calcium hydride under nitrogen
atmosphere. Column chromatography purifications were carried
out using silica gel (70-230 mesh). 1H NMR spectra were
recorded at 200, 300, or 500 MHz, and 13C NMR spectra were
recorded at 75 or 125 MHz. Peak assignments of NMR spectra
were determined using DEPT and two-dimensional experiments.
(7a R )-1,2,5,6,7,7a -H e xa h yd r op yr r olo[2,1,5-cd ]in d oli-
zin e (1). A suspension of LiAlH4 (1.5 g, 39 mmol) in dry 1,4-
dioxane (30 mL) was added to a stirred solution of (7aR)-5,6,7,7a-
tetrahydro-1H-pyrrolo[2,1,5-cd]indolizin-2-one3 (1 g, 6.20 mmol)
in the same solvent (30 mL) under N2 at room temperature. The
resulting mixture was heated under reflux for 20 h and then
cooled to 0 °C and quenched slowly with a saturated aqueous
Na2SO4 solution. After filtration, the organic layer was dried
and evaporated. Column chromatography on silica gel (pentane/
1
In a (1H, H) COSY experiment, we started from the character-
istic position of the H-7a atom (δ ) 3.81-3.87 ppm) to establish
the chemical shifts of all aliphatic protons. The obtained results
were confirmed by NOE experiments. In a next step, GHMQC
signals of H-2/C-2 allowed us to determined the C-2 chemical
shift at δ ) 23.1 ppm. Finally, GHMBC experiments displayed
a long-range correlation between the C-2 and H-3 at δ ) 6.17
ppm. All these results were in good agreement with the proposed
structure. The structure of the other obtained regioisomers was
determined in a similar way.
(7a R)-3-Acetyl-1,2,5,6,7,7a -h exa h yd r op yr r olo[2,1,5-cd ]in -
1
d olizin e (3b): IR (NaCl) 1657 (CO) cm-1; H NMR (500 MHz;
CDCl3) δ 1.27-1.33 (m, 1H, H-7), 1.76-1.79 (m, 1H, H-6), 1.87-
1.89 (m, 1H, H-6), 2.16-2.19 (m, 1H, H-1), 2.18-2.21 (m, 1H,
H-7), 2.35 (s, 3H, CH3), 2.57-2.59 (m, 1H, H-5), 2.60-2.62 (m,
2H, H-1), 2.70-2.72 (m, 1H, H-5), 2.84-3.45 (m, 1H, H-2), 3.86-
3.89 (m, 1H, H-7a), 6.19 (s, 1H, H-4); 13C NMR (75 MHz; CDCl3)
δ 20.1 (C-6), 21.6 (C-5), 23.1 (C-2), 25.1 (CH3), 27.8 (C-7), 35.6
(C-1), 54.1(C-7a), 105.3 (C-3), 116.1 (C-4), 121.2,131.6, 194.2
(CO).
CH2Cl2, 9:1) of the residue gave 1 (765 mg, 86% yield): [R]20
)
D
+111.0 (c 0.50, CH2Cl2); 1H NMR (300 MHz; CDCl3) δ 1.29-
1.55 (m, 1H, H-1), 1.78-1.89 (m, 1H, H-7), 2.02-2.09 (m, 1H,
H-6), 2.09-2.17 (m, 1H, H-7), 2.17-2.25 (m, 1H, H-1), 2.55-
2.64 (m, 1H, H-6), 2.64-2.72 (m, 2H, H-2), 2.72-2.98 (m, 2H,
(7a R)-4-F or m yl-1,2,5,6,7,7a -h exa h yd r op yr r olo[2,1,5-cd ]-
in d olizin e (6a ): [R]20D ) +99.4 (c 0.50, CH2Cl2); IR (NaCl) 1657

Notes
J . Org. Chem., Vol. 66, No. 7, 2001 2525
(CO) cm-1; 1H NMR (500 MHz; C6D6) δ 1.24-1.32 (m, 1H, H-7),
1.68-1.85 (m, 1H, H-6), 1.96-2.06 (m, 1H, H-1), 2.07-2.12 (m,
1H, H-6), 2.12-2.22 (m, 1H, H-7), 2.56-2.63 (m, 1H, H-1), 2.75-
2.87 (m, 2H, H-2), 2.87-2.93 (m, 1H, H-5), 3.16-3.19 (m, 1H,
H-5), 3.82-3.90 (m, 1H, H-7a), 6.21 (s, 1H, H-3), 9.67 (s, 1H,
CHO); 13C NMR (75 MHz; CDCl3) δ 20.1 (C-6), 21.2 (C-5), 24.5
(C-2), 28.8 (C-7), 37.1 (C-1), 54.7 (C-7a), 101.6 (C-3), 125.2 (C-
4), 132.1, 133.4, 184.0 (CO); MS (CI) 176 (MH.+). Anal. Calcd
for C11H13NO: C, 75.40; H, 7.40; N, 7.99. Found: C, 75.24; H,
7.37; N, 7.98.
as a mixture with its isomer 8b (see Table 1). 8b was character-
ized by its H-3 chemical shift at δ ) 6.23 ppm.
(7a R)-4-Eth yl-1,2,5,6,7,7a -h exa h yd r op yr r olo[2,1,5-cd ]in -
d olizin e (10). A 1 M solution of methyllithium in diethyl ether
(0.270 mL, 0.43 mmol) was added at 0 °C to a solution of
aldehyde 6a (0.50 g, 0.39 mmol) in THF (5 mL). The resulting
mixture was stirred under N2 at 0 °C for 30 min and at room
temperature for 30 min. THF was then evaporated, and the
crude product was dissolved in 1,4-dioxane (5 mL). A suspension
of AlLiH4 (0.70 g, 1.74 mmol) in dioxane (5 mL) was carefully
added. The solution was then stirred at 88 °C for 3 h, cooled at
0 °C, and quenched slowly with a saturated aqueous Na2SO4
solution. After filtration, the organic layer was dried (MgSO4)
and evaporated. Column chromatography on silica gel (pentane/
CH2Cl2, 9/1) of the residue gave pure compound 10 (yield: 72%).
The obtained 1H and 13C NMR spectra were in agreement with
those in the litterature.3
(7a R)-3,4-Difor m yl-1,2,5,6,7,7a -h exa h yd r op yr r olo[2,1,5-
cd ]in d olizin e (6c): [R]20D ) +108.8 (c 0.25, CH2Cl2); IR (NaCl)
1665 (CO) cm-1 1H NMR (300 MHz; CDCl3) δ 1.26-1.41 (m,
;
1H, H-7), 1.86-1.92 (m, 1H, H-6), 2.09-2.13 (m, 1H, H-1), 2.13-
2.19 (m, 1H, H-6), 2.19-2.28 (m, 1H, H-7), 2.68-2.74 (m, 1H,
H-1), 2.74-2.88 (m, 2H, H-2), 2.88-3.11 (m, 2H, H-5), 3.91-
4.07 (m, 1H, H-7a), 10.11 (s, 1H, CHO), 10.03 (s, 1H, CHO); 13
C
(7a R)-4-E t h yl-3-for m yl-1,2,5,6,7,7a -h exa h yd r op yr r olo-
[2,1,5-cd ]in d olizin e (11). The experimental procedure was
similar to the one reported for the formylation of 1: yield 80%;
NMR (75 MHz; CDCl3) δ 20.0 (C-6), 21.6 (C-2), 25.1 (C-5), 28.6
(C-7), 36.5 (C-1), 55.9 (C-7a), 117.9, 121.9, 135.1, 142.9, 185.8
(CO); 186.4 (CO); MS (CI) 204 (MH.+). Anal. Calcd for C12H13
-
[R]20 ) +94.2 (c 0.5, CH2Cl2); IR (NaCl) 1665 (CO) cm-1 1H
;
NO2: C, 70.92; H, 6.45; N, 6.89. Found: C, 70.66; H, 6.55; N,
6.93.
D
NMR (300 MHz; CDCl3) δ 1.24 (t, J ) 4.8 Hz, 3H, CH3), 1.27-
1.38 (m, 1H, H-7), 1.69-1.84 (m, 1H, H-6), 1.93-2.10 (m, 1H,
H-1), 2.12-2.21 (m, 2H, H-7 and H-6), 2.40-2.89 (m, 5H, H-1,
2H-5, CH2), 2.92-3.06 (m, 2H, H-2), 3.78-3.80 (m, 1H, H-7a),
9.74 (s, 1H, CHO); 13C NMR (75 MHz; CDCl3) δ 15.6 (CH3), 18.3
(CH2), 19.4 (C-5), 22.1 (C-6), 24.3 (C-2), 29.2 (C-7), 36.3 (C-1),
56.0 (C-7a), 116.6, 121.3, 123.9, 141.5, 184.4 (CO). Anal. Calcd
for C13H17NO: C, 76.81; H, 8.43; N, 6.89. Found: C, 76.79; H,
8.46; N, 6.88.
(7a R)-4-Eth yl-1,2,5,6,7,7a -h exa h yd r o-3-p r op en ylp yr r olo-
[2,1,5-cd ]in d olizin e M215A/B. NaH (1.07 mmol) was added to
a solution of (ethyl)triphenylphosphonium bromide (0.4 g,1.07
mmol) in THF (5 mL). A solution of aldehyde 11 (0.128 g, 0.63
mmol) in THF (5 mL) was then carefully added, and the
resulting mixture was refluxed for 12 h. The reaction was
quenched with water. The organic layer was dried (MgSO4) and
evaporated. Column chromatography on silica gel (CH2Cl2) of
the residue gave M215 A/B (4/1) (yield: 78%). The obtained 1H
and 13C NMR spectra were in agreement with those in the
litterature.1
(7a R)-1,2,5,6,7,7a -Hexa h yd r o-4-p r op ion ylp yr r olo[2,1,5-
cd ]in d olizin e (7a ): IR (NaCl) 1646 (CO) cm-1 1H NMR (500
;
MHz; CDCl3) δ 1.16 (t, J ) 7.5 Hz, 3H, CH3), 1.21-1.37 (m, 1H,
H-7), 1.69-1.80 (m, 1H, H-6), 1.87-2.01 (m, 1H, H-1), 2.09-
2.20 (m, 2H, H-6 and H-7), 2.54-2.60 (m, 1H, H-1), 2.66 (q, 2H,
CH2), 2.67-2.77 (m, 1H, H-2), 2.77-2.83 (m, 2H, H-3), 2.83-
2.87 (m, 1H, H-5), 3.09-3.22 (m, 1H, H-5), 3.66-3.85 (m, 1H,
H-7a), 6.18 (s, 1H, H-3); 13C NMR (75 MHz; CDCl3) δ (ppm) 21.3
(C-6), 23.0 (C-5), 24.4 (C-2), 28.8 (C-7), 32.7 (CH2), 37.6 (C-1),
55.2 (C-7a), 101.0 (C-3), 118.0 (C-1), 122.6, 130.7, 197.1 (CO);
MS (CI) 204 (MH.+). This compound was obtained as a mixture
with its isomer 7b (see Table 1). 7b was characterized by its
H-2 chemical shift at δ ) 6.21 ppm.
(7a R)-4-(3-Meth ylp r op ion yl)-1,2,5,6,7,7a -h exa h yd r op yr -
r olo[2,1,5-cd ]in d olizin e (8a ): IR (NaCl) 1648 (CO) cm-1 1H
;
NMR (300 MHz; CDCl3) δ 1.48 (d, J ) 2.7 Hz, 3H, CH3), 1.50
(d, J ) 2.7 Hz, 3H, CH3), 1.65-1.78 (m, 1H, H-7), 1.73-1.80
(m, 1H, H-6), 2.01-2.11 (m, 1H, H-1), 2.11-2.22 (m, 2H, H-7
and H-6), 2.56-2.63 (m, 1H, H-1), 2.75-2.99 (m, 3H, 2H-2 and
CH(CH3)2), 3.09-3.21 (m, 2H, H-5), 3.82-3.94 (m, 1H, H-7a),
6.20 (s, 1H, H-3); 13C NMR (75 MHz; CDCl3) δ 19.3 (CH3), 19.5
(CH3), 21.4 (C-6), 23.1 (C-5), 24.5 (C-2), 26.7 (C-7), 29.3 (C-1),
37.1 (CH), 55.4 (C-7a), 101.2 (C-3), 119.6 (C-4), 132.2, 138.1,
200.3 (CO); MS (CI) 218 (MH.+). This compound was obtained
Su p p or tin g In for m a tion Ava ila ble: NMR spectra of
obtained compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O001769X